This proposal requests support for a new research project to study the medicinal chemistry of four naturally occurring antitumor iridoids: allamandin (NSC 251691), penstemide, sarracenin and xylomollin. The first three of these iridoids have moderate antitumor effects in animal test systems (T/C approximately equal to 150 to 185 against P 388 lymphocytic leukemia). Since these four substances are not readily available from natural sources, this proposal outlines synthetic approaches to these iridoids via a common bicyclic synthon, or from other readily available iridoid glucosides. These will enable efficient preparation of the parent compounds and their analogues in racemic and chiral form. This project principally aims to understand how such compounds exert their antitumor effects on living systems. Initial work will examine the comparative antitumor activity of the parent compounds and appropriate analogues on macro systems in vitro (cell death) and in vivo (increase in rodent life span). These experiments will probe the premise that these iridoids are electrophilic substances, capable of alkylating vital biological molecules. Structure-activity relationships will provide a partial answer to this question. Subsequent experiments will examine the interaction of labeled forms of the compounds with subcellular systems to substantiate the premise of alkylating ability and to further define the molecular mechanism of action of these iridoids. The medicinal chemistry of antitumor iridoids is largely unexplored. Successful realization of the goals proposed should significantly enhance our knowledge about these novel antitumor agents.